Transgenic animal models are already available, as valuable tools for clarifying disease processes and identifying and characterizing pharmaceuticals which have a prophylactic or therapeutic effect, for a variety of disease types. The prerequisite for developing such animal models is, in particular, knowledge of genes which are involved in the given disease processes.
Aside from Alzheimer's disease, Parkinson's disease is the most well known disease in the neurodegenerative disease group. It is characterized by (1) a slowing down of all movements (bradykinesia), quiet and monotonous speech (akinesia or hypokinesia), absence of the physiological associated movements, a stooped posture, a small-step, partially shuffling gait, handwriting which becomes smaller as the writing continues, uncontrollable disturbances in movement, with a tendency to fall forward to the side or backward, (2) rigidity of the musculature (rigor), and (3) coarse resting tremor (trembling). Parkinson's disease is a disease which occurs relatively frequently and develops in approx. 1% of individuals aged over 60, in particular in men. The disease is caused by loss of dopamine in the striatum, resulting in the degeneration of neurons in the substantia nigra. The primary reason for loss of dopamine is not known (Dunnett and Björklund, 1999; Olanow and Tafton, 1999). Although the appearance of Parkinson's disease is sporadic as far as most patients are concerned, there is a small group of patients in whose families the disease occurs frequently. Molecular-genetic analyses performed in these families have led to the identification of several genes which, having been altered by mutations, are causatively involved in the onset of Parkinson's disease. One of these genes, which was discovered in 1998 by Nobuyoshi Shimizu, Yoshikuni Mizuno and their coworkers, has since then been designated Parkin or PARK2 (Kitada et al., 1998; Hattori et al., 1998). This gene was found to be mutated in several families in which several family members had developed autosomal recessive juvenile (beginning before the 40th year of life) Parkinson's disease. The protein of the Parkin gene is characterized, inter alia, by an ubiquitin domain in the N terminus, two RING finger-like motifs in the C terminus and an IBR (in between ring fingers) domain.
Another gene which has also been identified as being causatively involved in Parkinson's disease is the α-synuclein gene (Polymeropoulos et al., 1997). α-Synuclein is found, in particular, in the fibrillary, intracytoplasmic inclusions (Lewy bodies) which appear in association with Parkinson's disease. Aside from the presynaptic protein (α-synuclein, a large number of proteins, such as ubiquitin and neurofilament are also represented in the Lewy bodies. Mutations (A53T and A30P) in the α-synuclein gene on human chromosome 4q21-q22 lead to an autosomally dominant form of Parkinson's disease (Polymeropoulos et al., 1997; Kruger et al., 1998). How these mutations are able to induce Parkinson's disease has still not been elucidated. The dominant inheritance pattern and the fact that α-synuclein is present in Lewy bodies in fibrillary aggregations whose formation can be accelerated by the two mutations points to toxicity as the mechanism (toxic gain of function). A recent study has identified a sequence of 12 amino acids in the middle of α-synuclein which is responsible for the aggregation in vitro and which is absent from the very similar protein β-synuclein, which is nonaggregating (Giasson et al., 2000). α-Synuclein has thus far only been identified in vertebrates, with threonine, instead of alanine, as is the case in humans, being found in position 53 of the amino acid sequence in all the species known to date (Clayton and George, 1998).
Transgenic animal models which express different variants of human α-synuclein have thus far been established in the mouse and in Drosophila. The neuronal expression of α-synuclein in the mouse leads to a progressive accumulation of α-synuclein in intraneuronal inclusions, which inclusions are not, however, of a fibrillary nature (Masliah et al., 2000). By contrast, transgenic flies, which express α-synuclein panneuronally, exhibit fibrillary inclusions, which resemble the Lewy bodies, a loss of dopaminergic neurons and impairment of locomotory functions (Feany and Bender, 2000). In this connection, there were no significant differences in the expression of the individual forms of α-synuclein (wt, A53T and A30P).